Medulloblastoma: The Pieces Snap Together

Building on prior research, St. Jude scientists discover two genes suspected to cause brain tumors in children. This discovery lays the foundation to expand targeted treatments.

By Maureen Salamon; Photos by Seth Dixon

The day before Zahaan Tambawala was diagnosed with the brain tumor medulloblastoma, he insisted on buying food for kids at a local orphanage with money from his own piggy bank.

The 7-year-old’s random act of kindness was actually one of a series of big-hearted deeds leading up to his diagnosis, including volunteering to help a new classmate adjust to school and asking to donate his hair to children with medical needs. Although Zahaan had always been outgoing and precocious, his parents were proud but a bit puzzled by their son’s actions.

But the couple was certain about one thing. For the finest follow-up care after surgery, they wanted to take their son to St. Jude Children’s Research Hospital.

“I was told St. Jude is one of the best places in the world, and that’s when our journey here began,” says Zahaan’s father, Murtuza.

Whether he’s poring over Lego instruction pamphlets or quizzing doctors about his medical care, Zahaan Tambawala is empowered by knowledge—which is why he learns and uses technical scientific terminology, participates in his own medical care and constantly questions how treatments work. It should come as no surprise the inquisitive second-grader says he plans to return to St. Jude as a scientist when he grows up.

Designing targeted therapies

After receiving a doctor’s referral, the Tambawala family traveled to St. Jude from their home in Singapore. Zahaan has undergone chemotherapy and highly precise proton radiation therapy. That cutting-edge treatment coincides with recent advances revealing the genomic landscape of the malignant brain tumor.

In the most comprehensive analysis yet of medulloblastoma, an international group of scientists led by St. Jude identified genomic changes responsible for more than 75 percent of the tumors. The researchers also discovered two new suspected cancer genes found exclusively in the least-understood disease subgroups.

Published in the journal Nature, the findings will aid efforts to develop desperately needed precision medicines combating medulloblastoma.

Current therapies are only partially tailored to which of the four disease subgroups affect a patient, but typically combine surgery, chemotherapy and radiation. A child’s prognosis depends greatly on the disease subgroup. These subgroups are named WNT, sonic hedgehog, Group 3 and Group 4.

About 95 percent of children in the WNT subgroup enjoy long-term survival, compared to about 50 percent of patients in Group 3. Overall, about 70 percent of patients survive beyond five years.

But both survival rates and treatment side effects need to improve drastically—an ambition fueling research all over the globe, says St. Jude cancer biologist and medulloblastoma expert Paul Northcott, PhD, co-first author of the new study.

“Standard therapies fall short because if you expose a child’s developing central nervous system to radiation, it can induce damage,” he says, explaining that thinking, memory and other cognitive skills can be affected.

“Likewise, chemotherapies target dividing cells, but a growing child may have many normal cells actively dividing,” he continues. “The movement is to develop more specific therapies that only target tumor cells, an oncogene that is over-expressed, or a signaling pathway that is activated in cells it shouldn’t be.”

In the most comprehensive analysis yet of medulloblastoma, an international group of scientists led by St. Jude identified genomic changes responsible for more than 75 percent of the tumors.

Paul Northcott, PhD (left), is co-first author of a study that discovered two new suspected cancer genes found exclusively in the least-understood medulloblastoma subgroups.

Data stacked upon data

This once-lofty goal is now within reach. Northcott and his colleagues built off some of their own prior research that uncovered “low-hanging fruit”—genes that mutate at a high frequency in medulloblastoma. In the latest study, the scientists discovered two new suspected cancer-fueling oncogenes altered only in Group 3 and Group 4 medulloblastoma, which account for 65 to 70 percent of all cases of the malignant brain tumor.

The pair of genes, KBTBD4 and PRDM6, had not previously been linked with any type of cancer. And previously, less than one-third of mutations driving Group 3 and Group 4 medulloblastoma had been identified.

“It’s a big discovery,” Northcott says. “You don’t expect to find new cancer genes in 2017. If you talked to the godfathers of cancer genomics, they would’ve basically said all of the important cancer genes had already been found.”

International collaboration was crucial to generate the large numbers of patients required to produce these insights. Teaming with the German Cancer Research Center and The Hospital for Sick Children in Toronto, among others, St. Jude investigators performed whole-genome or whole-exome sequencing on tumor and normal tissue collected from 491 medulloblastoma patients. The genome is the complete set of genetic information carried inside nearly all cells.

This data was then layered with epigenetic data—chemical modifications to DNA that regulate genes—from 1,256 patients and gene expression data from 392 tumors.

“We covered all of the main attributes of the cancer at the molecular level,” Northcott explains. “Each on its own is powerful and gives a snapshot of what could be contributing to the cancer. But what I and many others realized is the utility of bringing these different data types together to make even further insights. Each of the individual components themselves couldn’t come to that conclusion.”

It’s a big discovery. You don’t expect to find new cancer genes in 2017.

If you talked to the godfathers of cancer genomics, they would’ve basically said all of the important cancer genes had already been found.

Paul Northcott, PhD

Under construction: Precision-based treatments

With the disease’s genetic and molecular underpinnings far better defined, the next logical step is to reclassify Group 3 and Group 4 medulloblastoma into a series of discrete subtypes. Northcott says he is excited to help design a new clinical trial testing various treatments in each of these subtypes.

“This will change the way we’re going to approach patients,” he says. “It’s really going to push us toward a precision-based approach. It’s another level of resolution we didn’t have before.”

Being at St. Jude has offered the Tambawalas a different sort of resolution, spurring personal growth and gratitude. The Lego-loving second-grader has become even more sympathetic to other children in need.

“We’ve seen him being compassionate, more than he was before,” Murtuza says. “I think he’s maturing through this episode in his life.”

Zahaan’s mom, Karishma, adds that she is especially thankful for the holistic approach to healing at St. Jude, which encompasses not only medical issues but also her son’s emotional and psychological needs.

The couple agree they couldn’t be more impressed and hopeful—both with Zahaan’s medulloblastoma treatment and the science fueling it.

“I have no words,” Murtuza says. “As parents, we obviously want to know where the cancer is coming from. St. Jude is at the forefront of it all.”